Professor Carl Smythe
Professor of Cell Biology
Director: Biological Mass Spectrometry Facility
Department of Biomedical Science
The University of Sheffield
Sheffield S10 2TN
Room: C106 Addison building
Telephone: +44 (0) 114 222 4643
Brief career history
Cellular surveillance systems and their role in healthy aging
Research in our laboratory uses molecular cell biology approaches to understand quality control or surveillance mechanisms that operate in cells to ensure fidelity of function, the consequences when they fail, and how they may be exploited to ameliorate disease. Examples include the replication checkpoint, which operates to ensure that cells experiencing replication stress, can evoke appropriate DNA damage responses, reschedule cell cycle events, or initiate apoptosis, and quality control systems regulating processes involving RNA homeostasis, such as nonsense-mediated decay (NMD), histone mRNA decay (HD), and telomere stability.
We utilise a variety of disease cell models in mechanistic studies and utilise whole genome and new chemical entity (NCE) screening together with mass spectrometry and imaging techniques, coupled with in vitro assays, to synergistically probe both biological and NCE function.
Our chemical biology work focuses on exploring the use of ruthenium co-ordination complexes to explore novel chemical space affecting pathways of interest, as well as novel indole polycyclic derivatives that block NMD.
Our focus is to identify potential new therapeutic targets in relevant disease models, and our work on the replication checkpoint has identified a number of proteins and /or pathways which are of interest.
A key focus concerns the functional characterisation of the DNA /RNA helicase Upf1 which acts pleiotropically to regulate NMD, HD and telomere integrity. We have identified a novel NMD inhibitor which, importantly, does not affect histone mRNA regulation or telomere integrity. We aim to utilise our expertise in genomic integrity and mass spectrometry to identify the target of this inhibitor as a potential therapeutic strategy for the treatment of nonsense mutation-associated disease.
Undergraduate and postgraduate taught modules
PhD Studentship Project
Novel genes required for checkpoint control and their role in colo arectal cancer
Co-Supervisor: Dr Mark Collins
Funding status: Awaiting funding decision/Possible external funding – find out more on our funding webpage.
Healthy aging is frequently affected by the onset of cancers. One in three of us will be affected over our lifetime, and 50% will have significantly reduced lifespan as a consequence. Cell cycle checkpoint genes are often mutated in cancers, while paradoxically, in appropriate circumstances, they may be attractive targets for rational drug design.
Our laboratory was one of the first labs to identify the significance of the Chk1 gene product in checkpoint control and have a significant interest in novel therapeutics and their identification. Colorectal cancer remains a significant challenge, often due to late presentation of symptoms and Chk1 inhibitors are currently in clinical trials for a subset of colorectal cancers. Recently we have undertaken a genome-wide siRNA screen in colorectal cancer cells to identify previously unknown checkpoint pathway genes in order to identify novel potential therapeutic targets. As a result we have identified novel genes whose roles in checkpoint regulation are completely unknown.
The aims of this project is to gain an understanding of the cellular function of one novel gene, which we have called MiCatS, in cellular checkpoint control. MiCatS-deficient cells appear to be unable to respond to cellular signalling pathways that indicate the presence of replication stress. This project will focus on developing an understanding of how MiCatS interferes with regulatory gene networks controlling genome integrity. Techniques: These will include a range of molecular cell biology techniques, tissue culture, confocal fluorescence microscopy, protein expression and functional characterisation approaches including proteomics, quantitative PCR, siRNA-mediated knockdown of gene expression, and immunoblotting.
(1) Feijoo, C., Hall-Jackson, C., Wu, R., Jenkins, D., Gilbert, D., and Smythe, C (2001). Activation of mammalian Chk1 during DNA replication arrest: a role for Chk1 in the intra-S phase checkpoint monitoring replication origin firing. The Journal of Cell Biology, 154(5), 913–924.
(2) Bowen, E., (2015). PhD Thesis. “A genomic screen for the identification of novel components of the S phase checkpoint”, University of Sheffield.
Keywords: Cancer / Oncology, Cell Biology / Development, Molecular Biology
For informal enquiries about the project or application process, please feel free to contact me.
For further information about projects within the department and how to apply, see our PhD Opportunities page:
- Gotham VJB, Hobbs MC, Burgin R, Turton D, Smythe C & Coldham I (2016) Synthesis and activity of a novel inhibitor of nonsense-mediated mRNA decay. Org. Biomol. Chem., 14(5), 1559-1563. View this article in WRRO
- Block KI, Gyllenhaal C, Lowe L, Amedei A, Amin ARMR, Amin A, Aquilano K, Arbiser J, Arreola A, Arzumanyan A, Ashraf SS, Azmi AS, Benencia F, Bhakta D, Bilsland A, Bishayee A, Blain SW, Block PB, Boosani CS, Carey TE, Carnero A, Carotenuto M, Casey SC, Chakrabarti M, Chaturvedi R, Chen GZ, Chen H, Chen S, Chen YC, Choi BK, Ciriolo MR, Coley HM, Collins AR, Connell M, Crawford S, Curran CS, Dabrosin C, Damia G, Dasgupta S, DeBerardinis RJ, Decker WK, Dhawan P, Diehl AME, Dong J-T, Dou QP, Drew JE, Elkord E, El-Rayes B, Feitelson MA, Felsher DW, Ferguson LR, Fimognari C, Firestone GL, Frezza C, Fujii H, Fuster MM, Generali D, Georgakilas AG, Gieseler F, Gilbertson M, Green MF, Grue B, Guha G, Halicka D, Helferich WG, Heneberg P, Hentosh P, Hirschey MD, Hofseth LJ, Holcombe RF, Honoki K, Hsu H-Y, Huang GS, Jensen LD, Jiang WG, Jones LW, Karpowicz PA, Keith WN, Kerkar SP, Khan GN, Khatami M, Ko YH, Kucuk O, Kulathinal RJ, Kumar NB, Kwon BS, Le A, Lea MA, Lee H-Y, Lichtor T, Lin L-T, Locasale JW, Lokeshwar BL, Longo VD, Lyssiotis CA, MacKenzie KL, Malhotra M, Marino M, Martinez-Chantar ML, Matheu A, Maxwell C, McDonnell E, Meeker AK, Mehrmohamadi M, Mehta K, Michelotti GA, Mohammad RM, Mohammed SI, Morre DJ, Muralidhar V, Muqbil I, Murphy MP, Nagaraju GP, Nahta R, Niccolai E, Nowsheen S, Panis C, Pantano F, Parslow VR, Pawelec G, Pedersen PL, Poore B, Poudyal D, Prakash S, Prince M, Raffaghello L, Rathmell JC, Rathmell WK, Ray SK, Reichrath J, Rezazadeh S, Ribatti D, Ricciardiello L, Robey RB, Rodier F, Rupasinghe HPV, Russo GL, Ryan EP, Samadi AK, Sanchez-Garcia I, Sanders AJ, Santini D, Sarkar M, Sasada T, Saxena NK, Shackelford RE, Shantha Kumara HMC, Sharma D, Shin DM, Sidransky D, Siegelin MD, Signori E, Singh N, Sivanand S, Sliva D, Smythe C, Spagnuolo C, Stafforini DM, Stagg J, Subbarayan PR, Sundin T, Talib WH, Thompson SK, Tran PT, Ungefroren H, Vander Heiden MG, Venkateswaran V, Vinay DS, Vlachostergios PJ, Wang Z, Wellen KE, Whelan RL, Yang ES, Yang H, Yang X, Yaswen P, Yedjou C, Yin X, Zhu J & Zollo M (2015) Designing a broad-spectrum integrative approach for cancer prevention and treatment. Seminars in Cancer Biology, 35, S276-S304. View this article in WRRO
- Ramu V, Gill M, Jarman P, Turton D, Thomas J, Das A & Smythe CG (2015) A Cytostatic Ruthenium(II)–Platinum(II) Bis(terpyridyl) Anticancer Complex That Blocks Entry into S Phase by Up-regulating p27KIP1. Chemistry - A European Journal, 21(25), 9185-9197. View this article in WRRO
- Novodvorsky P, Watson O, Gray C, Wilkinson RN, Reeve S, Smythe C, Beniston R, Plant K, Maguire R, M. K. Rothman A, Elworthy S, van Eeden FJM & Chico TJA (2015) klf2ash317 Mutant Zebrafish Do Not Recapitulate Morpholino-Induced Vascular and Haematopoietic Phenotypes. PLOS ONE, 10(10), e0141611-e0141611. View this article in WRRO
- Baggaley E, Gill MR, Green NH, Turton D, Sazanovich IV, Botchway SW, Smythe C, Haycock JW, Weinstein JA & Thomas JA (2014) Dinuclear ruthenium(II) complexes as two-photon, time-resolved emission microscopy probes for cellular DNA.. Angew Chem Int Ed Engl, 53(13), 3367-3371. View this article in WRRO
- Gill MR, Garcia-Lara J, Foster SJ, Smythe C, Battaglia G & Thomas JA (2009) A ruthenium(II) polypyridyl complex for direct imaging of DNA structure in living cells. NAT CHEM, 1(8), 662-667.
- Müller B, Blackburn J, Feijoo C, Zhao X & Smythe C (2007) DNA-activated protein kinase functions in a newly observed S phase checkpoint that links histone mRNA abundance with DNA replication. Journal of Cell Biology, 179(7), 1385-1398. View this article in WRRO
- Bolderson E, Scorah J, Helleday T, Smythe C & Meuth M (2004) ATM is required for the cellular response to thymidine induced replication fork stress.. Hum Mol Genet, 13(23), 2937-2945.
- Feijoo C, Hall-Jackson C, Wu R, Jenkins D, Leitch J, Gilbert DM & Smythe C (2001) Activation of mammalian Chk1 during DNA replication arrest: a role for Chk1 in the intra-S phase checkpoint monitoring replication origin firing. JOURNAL OF CELL BIOLOGY, 154(5), 913-923. View this article in WRRO